Presentation on theme: "Modification of the NAD+/NADH ratio to mimic Calorie Restriction Alan Cash Terra Biological LLC."— Presentation transcript:
Modification of the NAD+/NADH ratio to mimic Calorie Restriction Alan Cash Terra Biological LLC
Part 1 - Mechanism of Action: Using Oxaloacetate to increase the NAD+/NADH Ratio thereby Mimicking the Calorie Restriction Metabolic State Part 2 - Current Applications of Oxaloacetate as a Nutritional Supplement Part 3- Potential Future Applications of Oxaloacetate as a Drug for Disease Part 4- Patient Profiles that may benefit
2009 Aging CELL “Oxaloacetate Supplementation Increases Lifespan in C. elegans through an AMPK/ FOXO-dependent pathway” 2009 Open Longevity Science “Oxaloacetic Acid Supplementation Mimics Calorie Restriction” 2010 Anti-Aging Therapeutics Chapter 6 “Modification of NAD+/NADH”
Benefits: Increases in average and maximal lifespan— up to a 40% increase is seen in mammals. Decreases in cancer incidence—up to a 55% decrease. Decreases in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Complete protection against type II diabetes. Reduction in cardiovascular risk and, in particular, atherosclerosis. Reduction in inflammatory diseases, such as auto-immune type diseases.
NAD + /NADH “ in calorie restriction, Lifespan “ Lin 2003, Easlon 2008 NAD+ Salvage “ human cell lifespan “ Van der Veer 2007 NAD+ precursors “ lifespan “ Belenky 2007 AMPK “ Lifespan “ NAD+/NADH “ AMPK “ Greer 2007, Rafaeloff-Phail 2004 Mitochondrial NAD+ “ Cell survival “ Yang 2007
How to increase the NAD+/NADH Ratio? Calorie Restriction (via glucose starvation) Prolonged Exercise (via Gluconeogenesis) Supplementation with oxaloacetic acid
98% Positive Directional Overlap for genes Changed in common. OAA
Gene SymbolGene Title Affy- matrix Gene Number Change in Gene Expression Calorie Restricted to Control Change in Gene Expression benaGene to ControlGene function Foxa1forkhead289130% Increase40% Increase regulation of transcription, DNA-dependent // inferred from electronic annotation Foxa3forkhead13370100% Increase70% Increase cell glucose homeostasis // inferred from mutant phenotype // regulation of transcription, DNA-dependent // inferred from mutant phenotype /// cellular response to starvation // inferred from mutant phenotype Foxq1forkhead6994110% Increase 210% Increase regulation of transcription, DNA-dependent // inferred from electronic annotation Foxq1forkhead30006190% Increase 220% Increase regulation of transcription, DNA-dependent // inferred from electronic annotation
Applications of Oxaloacetate as a Nutritional Supplement
73 year-old European Woman Currently on Anti-Diabetic medicines Diaprel MR/ (80 mg)- 2 per day – Extended release Gliclazide (80 mg), a once per day diabetic drug Merckformin (1,000 mg)- 1 per day- (Metformin, Glucophage) – used for Type 2 diabetes Avandamet- 1 per day- a combination of metformin and rosiglitazone used for diabetes
Fasting glucose levels dropped 23%. Glucose levels after a meal dropped 34.5%, indicating a major improvement in glucose management and glucose tolerance. Metformin use reduced by 50% during the study. Results are statistically significant.
20-30% Decrease in Genes that Create & Store Fat 29% Reduction in Fat Tissue Mass with OAA Supplementation
Reduced Weight Rebound Due to Lower Gene Expression
OAA protects mitochondrial DNA in the brain Yamamoto 2003 retinal pigmented epithelium (RPE), damaged in age-related macular degeneration (AMD) are protected by zinc and OAA Wood 2003 pancreatic islet cells and neurons are protected by OAA Chang 2003, Berry 2006 OAA is a powerful anti-oxidant Desagher 1997, O’Donnell-Tormey 1987
10% increase in Muscle Endurance with OAA AMPK activation as Precursor to Mitochondrial Biosynthesis *
Potential Future Applications for Oxaloacetate as a Drug for Disease Treatment
Potential Support for: Cancer Alzheimer’s Parkinson’s Stroke Epilepsy Diabetes Animal Data looks good, but still early in the research effort. These statements have not been evaluated by the FDA. Oxaloacetate is not intended to diagnose, treat, cure or prevent any disease.
Calorie Restriction decreases cancer risk Currently one of the most effective broad-based methods to reduce cancer risk Oxaloacetic Acid Supplementation prevents Human Lung Cancer cells from reproducing In vitro results Does not affect normal cells Prevents replication of cancer cells by increasing intercellular debris, but does not kill the cells. Cancer cells did not reproduce after OAA solution removed for six weeks. Farah 2007
OAA Reduces Glioblastoma Tumor Growth by 50% Rubin, Inv. New Drugs 2012
21 day tumor growth in nude mice. Ruban, Investigative New Drugs 2012
Temozolomide And Oxaloacetate Rubin, Invest. New Drugs 2012 No tumor cells found In Remaining Mice.
After Review, US FDA Designates Oxaloacetate As an “Orphan Drug” for the Treatment of Gliomas. Designation (12-3704)
Substantial Improvement in Quality of Life Patient QOL Impact Score Improved From 79 to 8
Effective in 54% of patients surveyed (N=13) In the Effective Group, the average improvement in Quality of Life score was 63% (P < 0.05) Range of improvement varied between 20% and 90% Currently in Phase II Clinical Trial, See http://clinicaltrials.gov/ct2/show/NCT01741701
Alzheimer Model Mice show memory improvements 50% Increase in Short-Term Memory (Pistel, 2013)
Patient Profiles that may receive benefit from oxaloacetate
As a Nutritional Supplement Anti-Aging – General Population Helps to maintain proper glucose function Weight Maintenance Reduces the “Rebound Effect” After Dieting Increases Endurance & Fights Fatigue Elderly Patients Fatigued Patients Athletes Mood swings within PMS Constipation Reduction Improves Mitochondrial Function
As an Experimental Drug Clinical Trial Parkinson’s Disease Glioblastoma Alzheimer’s Disease 2-hydroxyglutaric aciduria Mitochondrial disease Diabetes Necessary for Clinical Trial IRB Approval Data sent to ClinicalTrials.gov Patient Approval Form 30-day FDA notification prior to the trial
Alan Cash Terra Biological LLC San Diego, CA 92130 858-947-5722 acash@benaGene.org Web: www.benaGene.com